Osmotic devices having composite walls

ABSTRACT

An osmotic device for delivering an active agent is disclosed. The device is comprised of a wall surrounding a compartment and has a passageway through the wall for releasing the agent. The wall is formed of a multiplicity of materials comprising a material permeable to an external fluid and substantially impermeable to agent and at least one additional material selected from a material that imparts stability to the wall, enhances the permeability of the wall to fluids, or aids in forming the wall. The compartment comprises an active agent that exhibits an osmotic pressure gradient against an external fluid, or the agent is mixed with an osmotically effective compound that exhibits an osmotic pressure gradient against the fluid. Agent is released from the device by fluid being imbibed through the wall into the compartment at a rate controlled by the permeability of the wall and the osmotic pressure gradient across the wall, to produce a solution containing agent that is released through the passageway at a controlled and continuous rate over a prolonged period of time.

FIELD OF THE INVENTION

This invention pertains to an osmotic device. More particularly, theinvention relates to an osmotic device having a wall formed of aplurality of semipermeable wall forming materials for delivering anactive agent at a controlled and continuous rate over a prolonged periodof time to an environment of use.

BACKGROUND OF THE INVENTION

Osmotic devices for delivering a beneficial agent to an environment ofuse are known to the prior art in U.S. Pat. Nos. 3,845,770 and3,916,899. The devices disclosed in these patents are made with a wallformed of a material that is permeable to an external fluid andsubstantially impermeable to agent. The wall surrounds a compartmentthat contains an agent and there is a passageway through the wall fordispensing the agent. These devices are remarkably effective fordelivering an agent that is soluble in the fluid and exhibits an osmoticpressure gradient across the wall against the fluid, and for deliveringan agent that has limited solubility in the fluid and is admixed with anosmotically effective compound soluble in the fluid that exhibits anosmotic pressure gradient across the wall against the fluid. The devicesrelease agent by fluid being continuously imbibed through the wall intothe compartment at a rate determined by the permeability of the wall andthe osmotic pressure gradient across the wall to produce a solution ofsoluble agent, or a solution of soluble compound containing agent whichsolution in either operation is dispensed from the device. While theabove devices represent a significant and pioneer advancement in the artand they are useful for dispensing numerous agents, there is anoccasional instance where the agent may have an unwanted effect on thedevice. For example, a wall formed of cellulose acetate having a lowacetyl content in the presence of certain agents can slowly loose itsintegrity over a prolonged period of time thereby slowly changing therate of imbibition and concomitantly the rate of agent release from thedevice over a correspondingly prolonged period of time.

OBJECTS OF THE INVENTION

Accordingly, it is an immediate object of this invention to provide animproved osmotic device for the controlled and continuous dispensing ofan active agent over a prolonged period of time which device overcomesthe problems known to the prior art.

Another object of the invention is to provide an osmotic device thatmaintains its physical and chemical integrity during the controlled andcontinuous dispensing of an agent over a prolonged period of time.

Yet another object of the invention is to provide an osmotic devicedesigned with a minimum number of parts and having at least one wallformed of a plurality of wall forming materials that makes the wallsubstantially inert towards agents and solutions thereof.

Another object of the invention is to provide an osmotic device fordispensing drugs that because of their inherent properties are difficultto dispense, and which drugs can be dispensed with the device of thisinvention at a controlled and continuous rate to perform their intendedtherapeutic effects.

Still a further object of the invention is to provide an osmoticdispensing system that can administer a complete pharmaceutical regimento a human for a particular time period, the use of which requiresintervention only for initiation and possibly termination of theregimen.

Still a further object of the invention is to provide osmotic deviceshaving a wide spectrum of semipermeable walls in which wall propertiessuch as the fluid flow-through rate and agent resistance may becontrolled and varied to the particular application.

Still another object of the invention is to provide an improved osmoticdevice for delivering drugs that are difficult to deliver and drugs thatrequire multiple doses, and which device can deliver the drugs over aprolonged period of time and also eliminate the necessity for takingmultiple doses of drug.

Yet still another object of the invention is to provide an osmoticdevice having a wall that has a high flux rate to fluids, a high degreeof exclusion towards agents and improved resistance to hydrolysis in thepresence of agents over a wide pH range.

Yet still another object is to provide an osmotic device that candeliver all kinds of drugs and has an economic advantage for the user bykeeping to a minimum the number of doses to be administered and reducingmissed doses because of forgetfulness.

Other objects, features and advantages of the invention will be moreapparent to those skilled in the art from the following specification,taken in conjunction with the drawings and the accompanying claims.

SUMMARY OF THE INVENTION

This invention concerns an osmotic device useful for dispensing anactive agent to an environment of use. The device is comprised of a wallsurrounding a compartment and has a passageway communicating with thecompartment and the exterior of the device. The compartment containseither an agent that exhibits an osmotic pressure gradient across thewall against an external fluid, or it contains a mixture of an agent andan osmotically effective compound that exhibits an osmotic pressuregradient across the wall against the fluid. The wall is comprised of ablend of a wall forming material with the wall being permeable to theexternal fluid, substantially impermeable to agent and substantiallyinert to agent and solutions thereof. Agent is dispensed from the deviceby fluid being imbibed through the wall into the compartment to dissolveagent or the compound and produce a solution that is released underosmotic pressure from the device through the passageway at a controlledand continuous rate over a prolonged period of time.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the figures are asfollows:

FIG. 1A is a view of an osmotic device designed for orally delivering abeneficial agent.

FIG. 1B is a view of the device of FIG. 1A in opened-section forillustrating the structure of the wall and the compartment of thedevice.

FIG. 2 is a view of an osmotic device manufactured for topicallyadministering drug.

FIG. 3 is a perspective view of another embodiment of the inventioncomprising a device shaped as an anal, osmotic drug delivery device.

FIG. 4 shows an osmotic device designed for releasing drug in thevaginal cavity.

FIG. 5 is a front view of the human eye illustrating an osmotic devicein operative position in the environment of use.

FIG. 6 is a view diagrammatically illustrating an osmotic devicedelivering drug to a drug receptor site.

FIG. 7 is a graph comparing a material that is inert with a materialthat slowly loses its integrity in the presence of agent.

FIG. 8 is a graph comparing the fluid flux through a wall that maintainsits integrity in the presence of fluid with a wall that slowly loses itsintegrity in the presence of fluid.

FIG. 9 represents the increase in fluid permeability of a materialcontaining a flux enhancer.

FIG. 10 represents the fluid permeability of films as a function ofincreased amounts of a flux enhancer which act as a wall stabilizer atthe same time.

FIG. 11 is a graph indicating the stability of films in the presence ofan agent.

FIG. 12 is a graph indicating the fluid permeability of a film comprisedof at least two wall forming materials.

FIG. 13 is a graph indicating the fluid permeability of a series offilms as a function of one of the substituting groups covalently bondedto a film forming material.

In the drawings and specification, like parts in related figures areidentified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further detailed elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail, which are examples of variousosmotic delivery devices of the invention, and which examples are not tobe considered as limiting, one example of an osmotic device is indicatedin FIGS. 1A and 1B, considered together, by numeral 10. Device 10 iscomprised of a body 11 having a wall 12 that surrounds a compartment 13,seen in FIG. 1B in opened-section with a portion of wall 12 removed at14, and a passageway 15 in wall 12 that communicates with compartment 13and the exterior of device 10. Compartment 13, as seen in FIG. 1B, inone embodiment is a means for containing an agent 16 that is soluble inan external fluid and exhibits an osmotic pressure gradient across wall12 against the fluid, or compartment 13 can contain a mixture of agentswith at least one agent exhibiting an osmotic pressure gradient. Inanother embodiment, compartment 13 contains an agent that has limitedsolubility or is substantially insoluble in the external fluid mixedwith an osmotically effective compound 17 that is soluble in theexternal fluid and exhibits an osmotic pressure gradient across wall 12against the fluid. Compartment 13 also can contain other compounds 17such as a surfactant for wetting the agent and a non-toxic dye foreither identifying the agent or for making release of agent visible tothe eye.

Wall 12 of device 10 is comprised in whole or in at least a part of acomposite of at least two wall forming materials blended to form a wallthat is, a) permeable to the passage of an external fluid, b)substantially impermeable to the passage of agent 16 and other compounds17 housed in compartment 13, c) is substantially inert in the presenceof agent 16, compound 17 and solutions thereof, and d) maintains itsphysical and chemical integrity in the environment of use during thedispensing of active agent. When wall 12 is formed in part of asemipermeable composite, the remainder of 12 is formed of a materialthat is substantially impermeable to fluid and to the passage of agent16 and compound 17 housed in compartment 13. A detailed description ofwall forming materials, agents and other compounds appears later in thespecification.

In operation in the environment of use, device 10 in one embodimentreleases agent 16 housed in compartment 13 and soluble in the externalfluid by fluid being imbibed into compartment 13 in a tendency towardsosmotic equilibrium at a rate controlled by the permeability of wall 12and the osmotic pressure gradient across wall 12 to continuouslydissolve agent 16 which is osmotically pumped from device 10 throughpassageway 15 at a controlled and continuous rate over a prolongedperiod of time. Device 10, in another embodiment, releases agent 16 thathas limited solubility in the fluid and is mixed with an osmoticallyeffective compound 17 by fluid being imbibed through wall 12 intocompartment 13 in a tendency towards osmotic equilibrium at a ratecontrolled by the permeability of wall 12 an the osmotic gradient acrosswall 12 to continuously dissolve compound 17 to form a solutioncontaining agent 16 which is pumped from device 10 through passageway 15at a controlled and continuous rate over a prolonged period of time.

Device 10 of FIGS. 1A and 1B can be made in many embodiments includingthe presently preferred embodiment for oral use, that is, for releasingin the gastrointestinal tract either a locally or systematically actingtherapeutic agent over a prolonged period of time. Oral device 10 canhave various conventional shapes and sizes such as round with a diameterof 3/16 inch to 1/2 inch, or it can be shaped like a capsule having arange of sizes from triple zero to zero, and from 1 to 8.

FIG. 2 represents another device 10 manufactured according to theinvention and designed for topically administering drug. Device 10 iscomprised of a semipermeable composite wall 12 surrounding acompartment, not shown, that contains an agent or a mixture of agent andan osmotically effective compound. Device 10 has two passageways forreleasing drug. Passageways 15 can be of the same or of different sizesso long as the total opened area lets device 10 operate as an osmoticdevice. Device 10 has a pair of integral straps optionally either coatedwith an adhesive for suitably mounting device 10 to the surface of ananimal, not shown, or straps 18 can have fastening strips of theVelcro®-type as disclosed in U.S. Pat. No. 3,086,529 on their ends forfastening device 10 around an arm or leg for administering drug thereto.It is sometimes preferred to fix one-half of each of the Velcro® stripson device 10 to mate with the opposite strip on strap 18. Device 10operates to release drug topically in the same way device 10 of FIGS. 1Aand 1B operate to release agent 16 to the environment of use.

FIG. 3 illustrates an osmotic device 10 designed for releasing an agentwithin a body opening, the anal canal not shown. Device 10 is shapedlike a tube and it has a lead end 19, a distant trailing end 22 and aplurality of circumferentially spaced ribs 23 extended along the lengthof device 10. Ribs 23 at end 22 unite with a downwardly facing shoulder20 that is formed with an annular removable closure 21 for fillingdevice 10. Ribs 23 serve to grasp the cellular wall of the anal canaland also to increase the exposed surface of device 10 for imbibing analfluid into the device. Wall 12 of device 10 is comprised of asemipermeable composite material and it surrounds a compartment, notshown, that contains an agent. A passageway 15 at end 19 extends throughwall 12 for releasing agent from the compartment to the exterior ofdevice 10. Device 10 of FIG. 3 releases either a locally or systemicallyacting agent in the anal canal in the same way device 10 of FIGS. 1A and1B release agent 16 to an environment of use.

FIG. 4 shows an osmotic device 10 within a vaginal tampon 24 that isdesigned for placement in a vagina. Tampon 24 has an elongated,cylindrical, precompressed, self-sustaining shape with a rounded leadend 25 and a slightly curved rear end 26. Tampon 24 is made of cottonwadding 28 and it is equipped with a manually controlled cord 27 foreasily removing it from a vagina. Tampon 24 serves as a platform forosmotic device 10. Device 10 is structurally identical with device 10 asdescribed above and it also operates in a like manner. Device 10 of FIG.4 in one embodiment contains a drug designed for absorption by thevaginal mucosa to produce a local or systemic effect. In anotherembodiment, device 10 contains an odor reductant that emits an odorcounteracting scent or fragrence in the vagina.

Referring to FIG. 5, device 10 is seen in an eye 28 for administeringdrug at an osmotically metered dosage rate. In FIG. 5, eye 28 iscomprised of an upper eyelid 29 with eyelashes 30 and a lower eyelid 31with eyelashes 32. Eye 28 anatomically is comprised of an eyeball 33covered for the greater part by sclera 34 and at its center area bycornea 35. Eyelids 29 and 31 are lined with an epithelial membrane orpalpebral conjunctiva, and sclera 34 is lined with a bulbar conjunctivathat covers the exposed surfaces of eyeball 33. Cornea 35 is coveredwith a transparent epithelial membrane. The portion of the palpebralconjunctiva which lines upper eyelid 30 and the underlying portion ofthe bulbar conjunctiva defines an upper cul-de-sac, while that portionof the palpebral conjunctiva which lines lower eyelid 31 and theunderlying portion of the bulbar conjunctiva defines a lower cul-de-sac.Ocular, osmotic device 10 is designed for placement in the upper orlower cul-de-sac. Device 10 is seen in the lower cul-de-sac and it isheld in place by the natural pressure of lower eyelid 31. Device 10contains an ophthalmic drug for osmotic release to eye 28.

Ocular device 10 can have any geometric shape that fits comfortably inthe cul-de-sac. Typical shapes include ellipsoid, bean, banana,circular, rectangular, doughnut, crescent and half-ring shaped devices.In cross-section, the devices can be doubly convex, concavo-convex,rectangular and the like, as the device in use will tend to conform tothe shape of the eye. The dimensions of an ocular device can vary widelywith the lower limit governed by the amount of drug to be supplied tothe eye as well as by the smallest sized device that can be placed intothe eye. The upper limit on the size of the device is governed by thespace limitation in the eye consistent with comfortable retention in theeye. Satisfactory devices generally have a length of 4 to 20millimeters, a width of 1 to 15 millimeters. The ocular device cancontain from 0.15 micrograms to 100 milligrams of drug, or more, and itis made from non-erodible and inert materials that are compatible withthe eye and its environment.

FIG. 6 diagrammatically illustrates the use of osmotic device 10. InFIG. 6, there is seen device 10 mounted on the arm 35 of a human foradministering drug thereto. Device 10 is connected through passageway15, not shown, to one end of a flexible conduit 36 which is connected atits other end to a needle 37 for releasing drug to drug receptor 38.Device 10 is structured and operates as previously described and itadministers drug at a controlled and continuous rate to receptor 38, theantecubital vein, not shown, for a prolonged period of time.

While FIGS. 1 through 6 are illustrative of various devices that can bemade according to the invention, it is to be understood these devicesare not to be construed as limiting, as the devices can take a widevariety of shapes, sizes and forms for delivering agent to differentenvironments of use. For example, the devices include buccal, implant,artificial gland, cervical, intrauterine and ear devices. The devicesalso can be adapted for delivering an active agent in streams,aquariums, fields, factories, reservoirs, laboratory facilities, hothouses, transportation means, navel means, air and military means,hospitals, veterinary clinics, nursing homes, chemical reactions, andother environments of use.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of the invention, it has now been foundthat device 10 can be manufactured with an improved wall(s) comprised ofat least two wall forming materials blended to form a wall that is, a)permeable to the passage of an external fluid present in the environmentof use, b) substantially impermeable to the passage of agent 16 andother compounds 17 housed in compartment 13, c) is substantially inertin the presence of agent 16, compounds 17 and solutions thereof, and d)maintains its physical and chemical integrity in the environment of useduring the dispensing of agent 16. Wall 12 is comprised of, 1) at leastone wall forming material permeable to the fluid and substantiallyimpermeable to agent 16 and other compounds 17 blended with at least oneor more of the following wall forming materials, 2) a stabilizingmaterial that imparts physical and chemical integrity to wall 12, andmore particularly gives wall 12 inertness towards agent 16, compounds17, solutions thereof, and to compounds present in the environment ofuse, 3) a flux enhancer that promotes the permeability of fluid throughwall 12, 4) a plasticizer that gives flexibility to the wall, and 5) adispersant useful for blending the materials into an operative integralcomposite wall. The wall's integrity or inertness to agents in thecompartment, and to fluids and other compounds in the environment of usecan, according to the mode and manner of the invention, be preciselyregulated by selecting the ingredients blended into the wall forming thedevice. The fluid permeability of the wall can be regulated in a likemanner. The term "composite" as used herein means the wall is comprisedof a blend of materials that act together to form the operative integralwall of the device.

Exemplary materials for forming wall 12 that are permeable to fluids andimpermeable to agents and impermeable to other compounds includemembranes known to the art as osmosis and reverse osmosis membranes.These membranes, that are useful for the purpose identified above by 1),generically include wall forming polysaccharides comprised ofanhydroglucose units. In one embodiment, the polysaccharides arecellulose esters having a degree of substitution, D.S., on theanhydroglucose unit from greater than 0 up to 3 inclusive. By "degree ofsubstitution" as used herein is meant the average number of hydroxylgroups on the anhydroglucose unit replaced by a substituting group.Exemplary materials are represented by Formula 1: ##STR1## wherein R₁,R₂ and R₃ are the same or different and they are selected from the groupconsisting of hydrogen and acyl, ##STR2## with at least one or all ofR₁, R₂ and R₃ in the anhydroglucose unit either partially or completelysubstituted with the acyl moiety. The acyl moiety at R₁, R₂ and R₃ canbe the same or different; and, R₄ is a member selected from the groupconsisting of hydrogen, alkyl groups of the straight or branched chaintype having from 1 to 20 carbons and alkenyl groups that are straight orbranched and have from 2 to 20 carbon atoms. Typical acyl moietiesinclude alkanoyl and alkenoyl such as formyl, acetyl, propionyl,butyryl, hexanoyl, heptanoyl, octanoyl, undecanoyl, lauroyl, palmitoyl,stearoyl, oleoyl, and isomeric forms thereof; and n in a presentlypreferred embodiment is a positive number greater than 5.

Representative materials embraced by Formula 1 include polymericcellulose esters and copolymeric cellulose esters such as mono, di, andtricellulose acylates. Exemplary polymers include cellulose acetatehaving a D.S. up to 1 and an acetyl content of up to 21%; cellulosediacetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%;cellulose triacetate having a D.S. of 2 to 3 and an acetyl content of 35to 44.8%; cellulose propionate having a D.S. of 1.8 and a propionylcontent of 38.5%; cellulose acetate propionate having an acetyl contentof 1.5 to 7% and a propionyl content of 39 to 42%; cellulose acetatepropionate having an acetyl content of 2.5 to 3%, an average combinedpropionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%;cellulose acetate butyrate having a D.S. of 1.8, an acetyl content of 13to 15%, and a butyryl content of 34 to 39%; cellulose acetate butyratehaving an acetyl content of 2 to 29.5%, a butyryl content of 17 to 53%,and a hydroxyl content of 0.5 to 4.7%; cellulose triacylates having aD.S. of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate,cellulose tripalmitate, cellulose trisuccinate, cellulose triheptylate,cellulose tricaprylate, cellulose trioctanoate, and cellulosetripropionate; cellulose diesters having a lower degree of substitutionprepared by the hydrolysis of the corresponding triester to yieldcellulose diacylates having a D.S. of 2.2 to 2.6 such as cellulosedisuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulosedicaprylate, and cellulose dipentanate; and esters prepared from acylanhydrides or acyl acids in an esterification reaction to yield esterssuch as cellulose acetate valerate, cellulose acetate succinate,cellulose propionate succinate, cellulose acetate octanoate, cellulosevalerate palmitate, cellulose acetate palmitate, and cellulose acetateheptanoate. Generally, the materials useful for forming the wall willhave a fluid permeability of 10⁻⁵ to 10⁻¹ (cc.mil/cm².hr.atm), expressedper atmosphere (atm) of hydrostatic or osmotic pressure differenceacross the membrane at the temperature of use while possessing a highdegree of impermeability to solute are useful for the purpose of theinvention. The polymers described above are known to the art or they canbe prepared according to the procedures in Encyclopedia of PolymerScience and Technology, Vol. 3, pages 325 to 354, 1964, published byInterscience Publishers Inc., New York.

The materials forming wall 12 will, in a presently preferred embodiment,include at least one material embraced by Formula 1. Wall 12 also caninclude a wall forming stabilizing material identified above as 2). Thislatter material is a different material than the wall forming materialand it is either selected from the materials embraced by Formula 1 or itis a material selected from those embraced by Formula 2 and othermaterials listed below. The materials embranced by Formula 2 also can beused as wall forming materials. When the latter is selected from Formula2, the stabilizer can be selected from the materials embraced byFormulae 1 or 2. Criterion that can be used for selecting the wallforming material and the stabilizing material from Formulae 1 and 2 andfrom other materials, are presented later in the specification.

The expressions "stabilizing material" and "wall forming stabilizingmaterial" as used herein further include materials embraced by Formula 2as follows: ##STR3## wherein R₅ is a member selected from the groupconsisting of hydroxyl; alkoxy; alkoxy substituted with a memberselected from the group consisting of alkyl, alkoxy, halogen and cyano;alkylcarbonate; alkylcarbamate; alkylsulfonate; alkylsulfamate;oxalkyleneoxycarboalkyl; acyloxy including alkanoyloxy, alkenoyloxy andaroyloxy; alkanoyloxy substituted with an alkoxy, halogen, carboalkyl,carboalkoxy and cyanoalkoxy; aroyloxy substituted with a halo, carboxy,carboalkyl and cyano; furoyloxy, and n is a positive integer greaterthan 5, usually 10 to 3 × 10⁶.

Exemplary groups representative of R₅ of Formula 2 are as follows: by"alkyl" is meant straight or branched chain alkyl radicals of 1 to 20carbon atoms inclusive, such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, pentyl, neo-pentyl, n-hexyl, iso-hexyl, heptyl,4,4-dimethyl pentyl, 2,2,4-trimethylpentyl, and nonyl. By "alkenyl" ismeant straight or branched chain alkenyl groups of 2 to 20 carbons suchas 1-propenyl, 2-propenyl or allyl, 1-butenyl, 2-butenyl, 1-pentenyl,and the corresponding positional isomers such as 1-isobutenyl,2-isobutenyl, 2-sec-butenyl, 2-methyl-1-butenyl, 2-methyl-2-pentyenyland 2,3-dimethyl-3-hexenyl. The term "alkoxy" as used for R₅ includedthe straight and branched chain alkoxy groups having 1 to 20 carbonsinclusive, for example, methoxy, ethoxy, propoxy, butoxy, n-pentoxy,n-hexoxy, isopropoxy, 2-butoxy, isobutoxy, 3-pentoxy, and n-octoxy.Exemplary halogen include fluorine, chlorine and bromine. Exemplary arylinclude phenyl and naphthyl. Exemplary alkylene as a linking moietywithin a substituent are alkylenes of 2 to 10 carbons such as1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,4-butylene, 1,5-pentylene,1,6-hexylene, 1,7-heptylene and 1,10-decylene. Exemplary alkanoyloxy,alkenoyloxy and aroyloxy include formyloxy, acetyloxy, propionyloxy,valeryloxy, heptanoyloxy, octanoyloxy, undecanoyloxy, lauroyloxy,palmitoyloxy, stearoyloxy, oleoyloxy, acryloyloxy, methacryloyloxy,crotomyloxy, 3-butenoyloxy, benzoyloxy, phenylacetyloxy, cinnamoyloxy,naphthoyloxy, p-ethoxybenzyloxy, alloxyphenylacetyloxy, furoyloxy,p-nitrobenzoyloxy and chlorophenoxyacetyloxy.

The stabilizing and wall forming materials embraced by Formula 2 includepolysaccharide materials having a degree of substitution on theanhydroglucose unit greater than from 0 up to 3 inclusive with thesubstituents at each R₅ the same or different. The materials can bepolymeric cellulose esters or polymeric cellulose ethers. The repeatingmonomeric unit can be substituted with like ester groups, with differentester groups, with like ether groups, with different ether groups andwith different ester and ether groups. Typical materials represented byFormula 2 include cellulose acetate acetoacetate, cellulose acetatechloroacetate, cellulose acetate furoate, dimethoxyethylcelluloseacetate, cellulose acetate carboxymethoxypropionate, cellulose acetatephthalate, cellulose butyrate naphthylate, cellulose acetate benzoate,methylcellulose acetate, methylcyanoethyl cellulose, cellulose acetatemethoxyacetate, cellulose acetate, cellulose acetate ethoxyacetate,cellulose acetate dimethylsulfamate, ethylcellulose dimethylsulfamate,cellulose acetate p-toluene sulfonate, cellulose acetatemethylsulfonate, cellulose acetate dipropylsulfamate, cellulose acetatebutylsulfonate, cellulose acetate dimethylaminoacetate, cellulosetriacetate, cellulose acetate ethyloxalate, mixed cellulose acetatelaurate, cellulose butyrate furoate, cellulose stearate, celluloseresinate, cellulose acetate methylcarbonate, cellulose acetateethylcarbonate, cellulose acetate methylcarbamate, and cellulose acetateethylcarbamate.

The stabilizing and wall forming materials also include cellulose etherssuch as alkylcellulose, methylcellulose, ethylcellulose,ethylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxyethyl methylcellulose, hydroxypropyl methylcellulose,ethylhydroxy ethylcellulose, hydroxybutyl methylcellulose,cyanoethylcellulose, benzylcellulose, sodium carboxymethylcellulose,sodium carboxymethylhydroxy ethylcellulose, carbamoylethylcellulose,carboxyethylcellulose, phenylcellulose, benzylhydrylcellulose,tritylcellulose, hexylpropylcellulose, carboxylbenzyl cellulose and2-carboxylbenzoyloxy propylcellulose. Method for preparing the celluloseethers are disclosed in Encyclopedia of Polymer Science and Technology,Vol. 3, pages 459 to 549, 1964, published by Interscience Publishers,Inc., New York.

Other materials useful as stabilizing materials and as wall formingmaterials include acrylated polysaccharides and acylated starches suchas agar-agar acetate, acylated alginates, amylose triacetate, betaglucan acetate, beta glucan triacetate, acetyl alginate, triacetate oflocust bean gum, alkanoyl carrageenin, acylated tragacanth, esterifiedgum karaya, cellulose derivatives substituted with an inorganic moietysuch as a nitro group, hydroxylated ethylene vinylacetate, aromaticnitrogen containing polymeric materials that exhibit permeability toaqueous fluids and substantially no passage to solute, semipermeablemembranes made from polymeric epoxides, copolymers of alkylene oxidesand alkyl glycidyl ethers, polyvinyl acetate, cross-linked polyvinylacetate, polyurethanes, film forming materials as disclosed by Loeb andSourirajan in U.S. Pat. No. 3,133,132, cross-linked derivatives ofpolyvinyl alcohol, polyvinyl butyrate, mixtures of polyvinyl acetate andcellulose esters, ionically associated polyelectrolytes formed by thecoprecipitation of a polycation and a polyanion as described in U.S.Pat. Nos. 3,276,586; 3,541,005; 3,541,006; 3,546,142; and 3,173,876;polystyrene derivatives such as poly(sodium styrene sulfonate) andpoly(vinylbenzyltrimethyl ammonium chloride), polyesters, polyamides andpolyacrylates. These materials and other materials are known to the artand disclosed in Handbook of Common Polymers by Scott, J. R. and Roff,W. J., 1971, published by CRC Press, Cleveland, Ohio.

Suitable wall forming materials for manufacturing an osmotic device canbe selected from the above materials according to the criteriondisclosed in U.S. Patent Application Ser. No. 440,281 filed Feb. 7,1974, now U.S. Pat. No. 3,916,899. This criterion consists in firstcalculating for a membrane that is to be selected, the permeability tofluid necessary to deliver an amount of agent Q_(p), in mg, in time t,in hours, from a device having a total membrane area A, in cm², amembrane thickness h, in mils, with the agent having a solubility in thefluid S, in mg/ml (solution), and the agent having an osmotic pressurein the device of π, in atm. The value k is expressed in units ##EQU1##and it is calculated from Equation 1. ##EQU2## Then, after havingcalculated the desired membrane permeability k from Equation 1,laboratory measurements are made to identify a wall forming materialcapable of forming a membrane having a permeability k_(o) substantiallyequivalent to the calculated permeability k. The measurements arecarried out by using a standard osmosis cell and measuring the rate offluid flow through a membrane made of wall forming material having aknown composition and thickness. The flow rate is determined bymeasuring fluid transport from a first chamber containing a fluid freeof agent through a membrane that separates it from a second chamberhousing a solution containing a known concentration of agent thatexhibits an osmotic gradient across the membrane. Sometimes the chambercontains an osmotically effective compound which is used as osmoticdriving agent. The flow measurement is preformed by adding to the firstchamber the fluid and then adding to the second chamber, equipped with astirring bar, the same fluid containing agent, and optionally containingthe additional osmotic agents. The first chamber is connected through aconduit to a reservoir containing a supply of fluid and the secondchamber is connected to a vertically positioned tube of known diameterand calibrated with indicia that indicate the amount of fluid in thetube. In operation, fluid flows from the first chamber through themembrane into the second chamber by osmosis causing the solution to risein the tube over time, t, to give a volume displacement, ΔV, during atime interval, ΔT. The volume, ΔV, is read on the tube calibrated incm³, and the time interval, Δt, is measured with a stopwatch. The valuek_(o) π in cm³.mil/cm².hr for the membrane with permeability, k_(o), forthe agent solution with an osmotic pressure, π, is calculated fromEquation 2, and wherein A_(o) is the area of the membrane, in thediffusion cell, and h_(o) is the thickness of this membrane. ##EQU3## Ifthe measured value, k_(o) π, approximates the calculated value, kπ, themembrane can be used for manufacturing the osmotic device. Otherprocedures and devices useful for measuring fluid permeability andosmotic flow are disclosed in J. App. Poly. Sci., Vol. 9, pages 1341 to1362, 1965; and in Yale J. Biol. Med., Vol. 42, pages 139 to 153, 1970.

Suitable stabilizing materials can be selected from the above materialsfor blending with the wall forming materials by those skilled in the artby using the procedures described below. These procedures are themembrane weight loss and the osmosis procedure. The procedures usemembranes formed with stabilizers and formed without stabilizers. Themembrane weight loss is carried out with membranes that are cast fromsolution or optionally melt pressed. The membranes are solution castwith a Gardner film-casting knife of a clean glass plate at roomtemperature with the solution removed by evaporation in an oven atelevated temperatures until the membranes are dry. Next, the membranesare removed from the glass and cut into strips 1 to 10 cm in length, 1to 10 cm in width and having a thickness of 1 to 10 mils. Then, afterall the strips are cut to have the same area and weight, they are placedin a glass container filled with a solution consisting of a knownconcentration of agent formulated with the fluid of the environment ofuse. The temperature of the container is made to correspond to thetemperature of the environment where an osmotic device formed with themembranes will be placed for releasing agents. At regular timeintervals, strips are taken form the solution, rinsed in distilledwater, dried in an oven, usually 50° C for 24 hours, and weighed. Theweight of a single strip repeatedly introduced into the solution, or theweight of many strips consecutively removed at different time intervalsare indicated along the ordinate, plotted as a function of timeindicated along the abscissa, such as t₁, t₂ , t₃, etc. as shown in FIG.7. In FIG. 7, line 1 represents the results obtained for a memrane thatmaintains its physical and chemical integrity when exposed to agentsolution. That is, the membrane does not lose any weight over time anddemonstrates inertness in the presence of agent solution. In the samefigure, line 2 represents a membrane which upon exposure to agentsolution, demonstrates a weight loss and is undesirable for making anosmotic device. A stabilizer can be blended into this membrane toenhance its inertness and substantially prevent weight loss therebymaking the membrane useful for fabricating devices.

In the osmosis procedure, the rate of fluid flow through a membrane ismeasured and it is performed using an osmosis cell. The purpose of theprocedure is to ascertain, (1) if a given membrane maintains itsintegrity in the presence of fluid and agent, and (2) if a stabilizeradded to the membrane increases its physical and chemical integrity asseen from flux measurements. The procedure is carried out using the cellaccording to the above described procedure with the volume of solution,ΔV, rising in the tube attached to chamber 2 measured and plotted as afunction of time, t. The data obtained for two different membranes areshown in FIG. 8. In FIG. 8, line 1 represents a membrane that maintainsits integrity in the presence of fluid and agent. That is, since therate of fluid flow is substantially constant, the membrane does notundergo any substantial change over time, t. Line 2 shows the fluidflux, ΔV/Δt, through a membrane where the rate is continually increasingover time. This change indicates the membrane does not maintain itsintegrity in the presence of fluid and agent. For those applicationswhere a change in flux is unwanted, a stabilizer can be added to themembrane to enhance its inertness. The flux through membranes containingstabilizer is measured as just described.

Using the above techniques, one versed in the art would use the weightloss and osmosis procedures for ascertaining if the fluid and agentadversely effect the membrane and also for determining if a stabilizerblended into the membrane overcomes this effect. The stabilizer can beadded in varying amounts to obtain an acceptable slope as seen in FIGS.7 and 8, with the stabilizer decreasing the slope, not shown, indicatinga lessening of membrane agent solution interaction.

Additional scientific criterious that can be used by those skilled inthe art for selecting a stabilizing material include the following: (a)the material possesses a high degree of substitution, for example, thematerial has undergone etherification or esterification particularlyacylation towards or to completion with membrane formed containing thesestabilizers demonstrate increased resistance to hydrolysis and increasedrejection of agent, (b) the stabilizer exhibits a flux decrease withincreasing molecular size of the substituting group, such as an ether orester group, (c) the stabilizer exhibits a flux decrease proportional tothe increase in size of the substituent, for example, the decreaseoccurs at the number of carbon atoms increase in a hydrocarbon moietysuch as an alkyl or alkoxy moiety, (d) the stabilizer exhibits increasedstability with an increase in the degree of substitution of hydrophobicether and larger hydrophobic ester groups with an accompanying decreasein the degree of substitution of smaller hydrophilic ester groups, and(e) the stabilizer exhibits a flux decrease as the number of polar,ionic groups bonded to the stabilizer decrease.

The expression "flux enhancing agent" as used herein means a compoundthat when added to a semipermeable wall forming material assists inregulating the fluid permeability or liquid flux through the wall. Theagent can be preselected to increase or decrease the liquid flow throughthe wall. Agents that produce a marked increase in permeability to fluidsuch as water, are often essentially hydrophilic, while those thatproduce a marked decrease to fluids such as water, are essentiallyhydrophobic. The flux enhancer in some embodiments also can increase theflexibility of the wall. The flux enhancers, in one embodiment, arepolyhydric alcohols and derivatives thereof, such as polyalkyleneglycols of the formula H-O-alkylene-OH wherein the bivalent alkyleneradical is straight or branched chain and has from 1 to 10 carbon atomsand n is 1 to 500 or higher. Typical glycols include polyethyleneglycols 300, 400, 600, 1500, 1540, 4000, and 6000 of the formula H-OCH₂CH₂ -OH wherein n is respectively 5 to 5.7, 8.2 to 9.1, 12.5 to 13.9, 29to 36, 29.8 to 37, 68 to 84, and 158 to 204. Other polyglycols includethe low molecular weight glycols such as polypropylene, polybutylene andpolyamylene.

The flux enhancing agents in another embodiment include poly(α,107)-alkylenediols wherein the alkylene is straight or branched chain offrom 2 to 10 carbon atoms such as poly(1,3)-propanediol,poly(1,4)-butanediol, poly(1,5)-pentanediol and poly(1,6)-hexanediol.The diols also include aliphatic diols of the formula HOC_(n) H_(2n) OHwherein n is from 2 to 10 and the diols are optionally bonded to anon-terminal carbon atom such as 1,3-butylene glycol, 1,4-pentamethyleneglycol, 1,5-hexamethylene glycol and 1,8-decamethylene glycol; andalkylenetriols having 3 to 6 carbon atoms such as glycerine,1,2,3-butanetriol, 1,2,3-pentanetriol, 1,2,4-hexanetriol and1,3,6-hexanetriol.

Other flux enhancers include esters and polyesters of alkylene glycolsof the formula HO--alkylene-O--H wherein the divalent alkylene radicalincludes the straight chain groups and the isomeric forms thereof havingfrom 2 to 6 carbons and n is 1 to 14. The esters and polyesters areformed by reacting the glycol with either a monobasic or dibasic acid.Exemplary flux enhancers are ethylene glycol dipropionate, ethyleneglycol butyrate, ethylene glycol diacetate, triethylene glycoldiacetate, butylene glycol dipropionate, polyester of ethylene glycolwith succinic acid, polyester of diethylene glycol with maleic acid andpolyester or triethylene glycol with adipic acid. Also, certainstabilizers in some embodiments can serve as a flux enhancerparticularly when it has a low D.S. of acyl moities.

Suitable flux enhancers for compounding with a material to increase itsfluid permeability can be selected by blending known amounts of anenhancer with the material, casting the blends into thin films, and thenmeasuring the increase in permeability towards the fluid found in theenvironment of use. For example, to two separate batches of wall formingcellulose acetate having an acetyl content of 32% and 39.8% were added1, 2 and 3 grams of flux enhancer polyethylene glycol having a molecularweight of 400 and the ingredients blended in a high shear blender in thepresence of 120 ml of dimethyl formamide to yield six blends. Next, theblends were solvent cast with a Gardener knife and dried in an oven for7 days at 50° C. The water permeability of the six films was measured inthe osmosis cell described above and the results recorded in FIG. 9. Inthe figure, the triangle represents cellulose acetate 32% and the circlerepresents cellulose acetate 39.8%. Also, as recorded on the ordinate,k_(o) indicates the water permeability through cellulose acetate 32%free of flux enhancer and cellulose acetate 39.8% that did not containany flux enhancer, and k indicates the water permeability throughcellulose acetate 32% and cellulose acetate 39.8% where both containedthe flux enhancer. The positive integers 10, 20, 30 and 40 recorded onthe abscissa, indicate the percent of flux enhancer in the film. Usingthe above technique, specific flux enhancers for blending with specificmaterials to regulate the permeability can be selected for making thedesired osmotic device. The amount of flux enhancer added to a materialgenerally is an amount sufficient to produce the desired permeability,and it will vary according to the wall forming material and the fluxenhancer used to regulate the permeability. Usually, from 0.001 parts upto 50 parts, or higher of flux enhancer can be used to achieve thedesired results, with a presently preferred range consisting of 0.1 partup to 30 parts of enhancer or mixtures thereof for 100 parts of wallforming material.

Exemplary plasticizers suitable for the present purpose genericallyinclude plasticizers that lower the temperature of the second-orderphase transition of the wall or the elastic modulus thereof; and alsoincrease the workability of the wall, its flexibility and itspermeability to fluid. Plasticizers operable for the present purposeinclude both cyclic plasticizers and acyclic plasticizers. Typicalplasticizers are those selected from the group consisting of phthalates,phosphates, citrates, adipates, tartrates, sebacates, succinates,glycolates, glycerolates, benzoates, myristates, sulfonamides, andhalogenated phenyls. Generally from 0.01 to 100 parts, or higher, of aplasticizer or a mixture of plasticizers are incorporated into 100 partsof wall forming material.

Exemplary plasticizers include dialkyl phthalates, dicycloalkylphthalates, diaryl phthalates and mixed alkyl-aryl phthalates asrepresented by dimethyl phthalate, dipropyl phthalate,di(2-ethylhexyl)-phthalate, di-isopropyl phthalate, diamyl phthalate anddicapryl phthalate; alkyl and aryl phosphates such as tributylphosphate, trioctyl phosphate, tricresyl phosphate, trioctyl phosphate,tricresyl phosphate and triphenyl phosphate; alkyl citrate and citrateesters such as tributyl citrate, triethyl citrate, and acetyl triethylcitrate; alkyl adipates such as dioctyl adipate, diethyl adipate anddi(2-methoxyethyl)-adipate; dialkyl tartrates such as diethyl tartrateand dibutyl tartrate; alkyl sebacates such as diethyl sebacate, dipropylsebacate and dinonyl sebacate; alkyl succinates such as diethylsuccinate and dibutyl succinate; alkyl glycolates, alkyl glycerolates,glycol esters and glycerol esters such as glycerol diacetate, glyceroltriacetate, glycerol monolactate diacetate, methyl phythayl ethylglycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate,ethylene glycol dibutyrate, triethylene glycol diacetate, triethyleneglycol dibutyrate and triethylene glycol dipropionate. Otherplasticizers include camphor, N-ethyl-(o- and p-toluene) sulfonamide,chlorinated biphenyl, benzophenone, N-cyclohexyl-p-toluene sulfonamide,and substituted epoxides.

Suitable plasticizers can be selected for blending with the wall formingmaterials by selecting plasticizers that have a high degree of solventpower for the materials, are compatible with the materials over both theprocessing and use temperature range, exhibits permanence as seen by itsstrong tendency to remain in the plasticized wall, imparts flexibilityto the material and are non-toxic to animals, humans, avians, fishes andreptiles. Produces for selecting a plasticizer having the describedcharacteristics are disclosed in the Encyclopedia of Polymer Science andTechnology, Vol. 10, pages 228 to 306, 1969, published by John Wiley &Sons, Inc. Also, a detailed description pertaining to the measurement ofplasticizer properties including solvent parameters and compatibilitysuch as the Hildebrand solubility parameter δ, the Flory-Hugginsinteraction parameter μ, and the cohesive-energy density, CED,parameters are disclosed in Plasticization and Plasticizer Processes,Advances in Chemistry Series 48, Chapter 1, pages 1 to 26, 1965,published by the American Chemical Society. The amount of plasticizeradded generally is an amount sufficient to produce the desired wall andit will vary according to the plasticizer and the materials. Usuallyabout 0.001 parts up to 50 parts, or higher, plasticizer can be used for100 parts of wall forming material with a presently preferred range of0.1 part to 20 parts of plasticizer, or mixtures thereof for 100 partsof wall forming materials.

Dispersants useful for the present purpose are those dispersants whenadded to a wall forming material and other materials aid in producing anintegral composite that is useful for making the operative wall of adevice. The dispersants act by regulating the surface energy ofmaterials to improve their blending into the composite. This lattermaterial is used for manufacturing devices that maintain there integrityin the environment of use during the agent release period. Generally,the dispersants are amphipathic molecules comprises of a hydrophobicpart and a hydrophilic part. The dispersants can be anionic, cationic,nonionic or amphoteric and they include anionics such as sulfatedesters, amides, alcohols, ethers and carboxylic acids; sulfonatedaromatic hydrocarbons, aliphatic hydrocarbons, esters and ethers;acylated amino acids and peptides; and metal alkyl phosphates; cationicdispersants such as primary, secondary, tertiary and quaternaryalkylammonium salts; acylated polyamines; and salts of heterocyclicamines, arylammonium dispersants such as esters of polyhydric alcohols,alkoxylated amines; polyoxyalkylene; esters and ethers ofpolyoxyalkylene glycols; alkanolamine fatty acid condensates; tertiaryacetylamic glycols; and dialkyl polyoxyalkylene phosphates; andampholytics such as betamines; and amino acids.

Typical dispersants include polyoxyethylenated glycerol ricinoleate;polyoxyethylenated caster oil having from 9 to 52 moles of ethyleneoxide; glycerol mannitan laurate, and glycerol (sorbitan oleates,stearates or laurates); polyoxyethylenated sorbitan laurate, palmitate,stearate, oleate or hexaolate having from 5 to 20 moles of ethyleneoxide; mono-, di- and poly-ethylene glycol stearates, laurates, oleates,myristates, behenates or ricinoleates; propylene glycol carboxylic acidesters; sorbitan laurate, palmitate, oleate, and stearate;polyoxyethylenated octyl, nonyl, decyl, and dodecylphenols having 1 to100 moles of ethylene oxide; polyoxyethylenated nonyl, lauryl, decyl,cetyl, oleyl and stearyl alcohols having from 3 to 50 moles of ethyleneoxide; polyoxypropylene glycols having from 3 to 300 moles of ethyleneoxide; sodium salt of sulfated propyl oleate; sodiumdi(heptyl)sulfosuccinate; potassium xylenesulfonate; 1:1 myristic aciddiethanolamide; N-coco-β-aminopropionic acid;bis(2-hydroxyethyl)tallowamine oxide;(diisobutylphenoxyethoxyethyl)dimethylbenzylammonium halide;N,N'-polyoxypropylenated ethylenediamine having a molecular weight from500 to 3000; tetraalkylammonium salts with up to 26 carbon atoms in thecation; sodium or potassium salt of polypeptide cocoanut, oleic orundecylenic acid condensate; metal salts of N-acylated short chainaminosulfonic acids; soybean phosphatides; and sulfobetaine.

Suitable dispersants can be selected from the above and from otherdispersants for blending with wall forming materials by using thedispersant's hydrophile-lipophile balance number, HLB. This numberrepresents the proportion between the weight percentages of hydrophilicand lipophilic groups in a dispersant. In use, the number indicates thebehavior of the dispersant, that is, the higher the number the morehydrophilic the dispersant and the lower the number the more lipophilicthe dispersant. The required HLB number for blending wall formingmaterials is determined by selecting a dispersant with a known number,blending it with the materials and observing the results. A homogenouscomposite is formed with the correct number; while a heterogenousmixture indicates a different number is needed. This new number can beselected by using the prior number as a guide. The HLB number is knownto the art for many dispersants, and they can be experimentallydetermined according to the procedure in J. Soc. Cosmetic Chem., Vol. 1,pages 311 to 326, 1949, or it can be calculated by using the procedurein J. Soc. Cosmetic Chem., Vol. 5, pages 249 to 256, 1954, and in Am.Perfumer Essent. Oil Rev., Vol. 65, pages 26 to 29, 1955. Typical HLBnumbers are set forth in Table 1. Generally a number of 10 or lessindicates lipophilic behavior and 10 or more indicates hydrophilicbehavior. Also, HLB numbers are algebraically additive. Thus, by using alow number with a higher number, blends of dispersants can be preparedhaving numbers intermediate between the two numbers. The amount ofdispersant needed is an amount that when blended with all formingmaterials will form the desired wall composite, and it will varyaccording to the particular dispersant and materials that are blended toform the wall. Generally, the amount of dispersant will range from about0.001 parts up to 40 parts, or higher, for 100 parts of wall formingmaterial with a presently preferred range of 0.1 part to 15 parts ofdispersant or mixtures thereof, for 100 parts of wall forming material.

                  TABLE 1                                                         ______________________________________                                        DISPERSANT             HLB NUMBER                                             ______________________________________                                        Sorbitan trioleate     1.8                                                    Polyoxyethylene sorbitol beeswax                                                                     2.0                                                    Sorbitan tristearate   2.1                                                    Polyoxyethylene sorbitol hexastearate                                                                2.6                                                    Ethylene glycol fatty acid ester                                                                     2.7                                                    Propylene glycol fatty acid ester                                                                    3.4                                                    Propylene glycol monostearate                                                                        3.4                                                    Ethylene glycol fatty acid ester                                                                     3.6                                                    Glycerol monostearate  3.8                                                    Sorbitan monooleate    4.3                                                    Propylene glycol monolaurate                                                                         4.5                                                    Diethylene glycol fatty acid ester                                                                   5.0                                                    Sorbitan monopalmitate 6.7                                                    Polyoxyethylene dioteate                                                                             7.5                                                    Polyoxypropylene mannitol dioleate                                                                   8.0                                                    Sorbitan monolaurate   8.6                                                    Polyoxyethylene lauryl ether                                                                         9.5                                                    Polyoxyethylene sorbitan monolaurate                                                                 10.0                                                   Polyoxyethylene lanolin derivative                                                                   11.0                                                   Polyoxyethylene glycol 400 monooleate                                                                11.4                                                   Triethanolamine oleate 12.0                                                   Polyoxyethylene nonyl phenol                                                                         13.0                                                   Polyoxyethylene sorbitan monolaurate                                                                 13.3                                                   Polyoxyethylene sorbitol lanolin                                                                     14.0                                                   Polyoxyethylene stearyl alcohol                                                                      15.3                                                   Polyoxyethylene 20 cetyl ether                                                                       15.7                                                   Polyoxyethylene 40 stearate                                                                          16.9                                                   Polyoxyethylene monostearate                                                                         17.9                                                   Sodium oleate          18.0                                                   Potassium oleate       20.0                                                   ______________________________________                                    

Exemplary solvents suitable for manufacturing the composite wall includeinert inorganic and organic solvents that do not adversely harm the wallforming materials and the final composite wall. The solvents broadlyinclude members selected from the group consisting of aqueous solvents,alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenatedsolvents, cycloaliphatic, aromatics, heterocyclic solvents and mixturesthereof. Typical solvents include acetone, diacetone alcohol, methanol,ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethylacetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone,methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethylether, ethylene glycol monoethyl acetate, methylene dichloride, ethylenedichloride, propylene dichloride, carbon tetrachloride, nitroethane,nitropropane, tetrachloroethane, ethyl ether, isopropyl ether,cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane,tetrahydrofuran, diglyme, water, and mixtures thereof such as acetoneand water, acetone and methanol, acetone and ethyl alcohol, methylenedichloride and methanol, and ethylene dichloride and methanol.

The expression "passageway" as used herein comprises means and methodssuitable for releasing the agent from the device. The expressionincludes an aperture, orifice or bore through the wall formed bymechanical procedures or by eroding an erodible element, such as agelatin plug, in the environment of use. A detailed description ofosmotic passageways and the maximum and minimum dimensions for apassageway are disclosed in U.S. Pat. No. 3,845,770 and in U.S. PatentApplication Ser. No. 440,281 filed Feb. 7, 1974, now U.S. Pat. No.3,916,899.

The osmotically effective compounds that can be used for the purpose ofthe invention include inorganic and organic compounds that exhibit anosmotic pressure gradient against an external fluid across the compositewall of the device. The compounds are used mixed with an agent that haslimited solubility in the external fluid with the compound forming asaturated solution containing agent that is osmotically delivered fromthe device. The phrase "limited solubility" as used herein means theagent has a solubility of about less than 1% by weight in the externalfluid. The compounds are used by homogenously or heterogenously mixingthe compound or a mixture of compounds with an agent, either before theyare charged into the reservoir, or by self-mixing after they are chargedinto the reservoir. In operation, these compounds attract fluid into thedevice producing a solution of compound which is delivered from thedevice concomitantly transporting undissolved and dissolved agent to theexterior of the device. Osmotically effective compounds useful for thepresent purpose include magnesium sulfate, magnesium chloride, sodiumchloride, lithium chloride, potassium sulfate, sodium carbonate, sodiumsulfite, lithium sulfate potassium chloride, calcium bicarbonate, sodiumsulfate, calcium sulfate, potassium acid phosphate, calcium lactated-mannitol, urea, inositol, magnesium succinate, tartaric acid,carbohydrates such as raffinose, sucrose, glucose, α-d-lactosemonohydrate, and mixtures thereof. The compound is initially present inexcess and it can be in any physical form such as particle, crystal,pellet, tablet, strip, film or granule. The osmotic pressure ofsaturated solutions of various osmotically effective compounds and formixtures of compounds at 37° C, in water, is listed in Table 2. In thetable, the osmotic pressure π, is in atmospheres, ATM. The osmoticpressure is measured in a commercially available osmometer that measuresthe vapor pressure difference between pure water and the solution to beanalyzed, and according to standard thermodynamic principles, the vaporpressure ratio is converted into osmotic pressure difference. In Table2, osmotic pressures of from 20 ATM to 500 ATM are set forth; of course,the invention includes the use of lower osmotic pressures from zero, andhigher osmotic pressures than those set forth by way of example in Table2. The osmometer used for the present measurements is identified asModel 302B, Vapor Pressure Osmometer, manufactured by the HewlettPackard Co., Avondale, Penna.

                  TABLE 2                                                         ______________________________________                                                               OSMOTIC                                                COMPOUND OR            PRESSURE                                               MIXTURE                ATM                                                    ______________________________________                                        Lactose-Fructose       500                                                    Dextrose-Fructose      450                                                    Sucrose-Fructose       430                                                    Mannitol-Fructose      415                                                    Sodium Chloride        356                                                    Fructose               355                                                    Lactose-Sucrose        250                                                    Potassium Chloride     245                                                    Lactose-Dextrose       225                                                    Mannitol-Dextrose      225                                                    Dextrose-Sucrose       190                                                    Mannitol-Sucrose       170                                                    Sucrose                150                                                    Mannitol-Lactose       130                                                    Dextrose               82                                                     Potassium Sulfate      39                                                     Mannitol               38                                                     Sodium Phosphate Tribasic . 12H.sub.2 O                                                              36                                                     Sodium Phosphate Dibasic . 7H.sub.2 O                                                                31                                                     Sodium Phosphate Dibasic . 12H.sub.2 O                                                               31                                                     Sodium Phosphate Dibasic Anhydrous                                                                   29                                                     Sodium Phosphate Monobasic . H.sub.2 O                                                               28                                                     ______________________________________                                    

The expressive "active agent" as used herein broadly includes anycompound, composition of matter or mixture thereof, that can bedelivered from the device to produce a beneficial and useful result. Theagent can be soluble in a fluid that enters the reservoir and functionsas an osmotically effective solute or it can have limited solubility inthe fluid and be mixed with an osmotically effective compound soluble influid that is delivered from the device. The active agent includespesticides, herbicides, germicides, biocides, algicides, rodenticides,fungicides, insecticides, anti-oxidants, plant growth promoters, plantgrowth inhibitors, preservatives, disinfectants, sterilization agents,catalysts, chemical reactants, fermentation agents, foods, foodsupplements, nutrients, cosmetics, drugs, vitamins, sex sterilants,fertility inhibitors, fertility promoters, air purifiers, micro-organismattenuators, and other agents that benefit the environment of use.

In the specification and the accompanying claims, the term "drug"includes any physiologically or pharmacologically active substance thatproduces a localized or systemic effect or effects in animals, includingmammals, humans and primates, avians, domestic household, sport or farmanimals such as sheep, goats, cattle, horses and pigs, for administeringto laboratory animals such as mice, rats and guinea pigs, and to fishes,reptiles and zoo animals. The active drug that can be delivered includesinorganic and organic compounds without limitation, those materials thatact on the cental nervous system such as hypnotics and sedatives,including pentobarbital sodium, phenobarbital, secobarbital, thiopentaland mixtures thereof, heterocyclic hypnotics such as dioxopiperidinesand glutarimides, hypnotics and sedatives such as amides and ureas,exemplified by diethylisovaleramide and α-bromoisovaleryl urea, hypnoticand sedative urethanes and disulfanes, psychic energizers such asisocarboxazid, nialamide, phenelzine, imipramine, tranylcypromide andparagylene, tranquilizers such as chloropromazine, promazine,fluphenazine, reserpine, deserpidine, meprobamate, benzodiazepines suchas chlordiazepoxide, anticonvulsants such as primidone, enitabas,diphenylhydantoin, ethltion, pheneturide and ethosuximide, musclerelaxants and antiparkinson agents such as mephenesin, methocarbomal,trihexylphenidyl, biperiden, levo-dopa also known as L-dopa andL-β-3-4-dihydroxypehnylalanine, analgesics such as morphone, codeine,meperidine, nalorphine, antipyretics and anti-inflammatory agents suchas aspirin, salicylamide, colchicine and sodium salicylamide, localanesthetics such as procaine, lidocaine, naepaine, piperocaine,tetracaine and dibucane, antispasmodics and muscle contractants such asatropine, scopolamine, methscopolamine, oxyphenonium, papaverine,prostaglandins such as PGE₁, PGE₂, PGF₁α, PGF₂α and PGA, anti-microbialssuch as penicillin, tetracycline, oxytetracycline, chlorotetracycline,chloramphenicol and sulfonamides, anti-malarials such as4-aminoquinolines, 8-aminoquinolines and pyrimethamine, hormonal agentssuch as prednisolone, cortisone, cortisol and triamcinolone, androgenicsteroids such as methyltestosterone, and fluoxmesterone, estrogenicsteroids such as 17β-estradiol, α-estradiol, estriol, α-estradiol3-benzoate, and 17-ethynyl estradiol-3-methyl ether, progestationalsteroids such as progesterone, 19-nor-pregn- 4-ene-3,20-dione,17-hydroxy-19-nor-17-α-pregn-5(10)-ene-20-yn-3-one,17α-ethynyl-17-hydroxy-5(10)-estren-3-one, and9β,10α-pregna-4,6-diene-3,20-dione, sympathomimetic drugs such asepinephrine, amphetamine, ephedrine and norepinephrine, cardiovasculardrugs such as procainamide, procainamide hydrochloride, amyl nitrile,nitroglycerin, dipyredamole, sodium nitrate and mannitol nitrate,diuretics such as chlorathiazide, acetazolamide, methazolamide andflumethiazide, antisparasitics such as bephenium, hydroxynaphthoate,dichlorophen and dapsone, neoplastics such as mechlorethamine, uracilmustard, 5-fluorouracil, 6-thioguanine and procarbazine, hypoglycemicdrugs such as insulin, isophane insulin, protamine zinc insulinsuspension, globin zinc insulin, extended insulin zinc suspension,tolbutamide, acetohexamide, tolazamide and chloropropamide, nutritionalagents such as ascorbic acid, niacin, nicotinamide, folic acid, choline,biotin, pantothenic acid, and vitamin B₁₂ essential amino acids,essential fats, eye drugs such as pilocarpine, pilocarpine salts such aspilocarpine nitrate,, pilocarpine hydrochloride, dichlorphenamide,atropine, atropine sulfate, scopolamine and eserine salicylate, andelectrolytes such as calcium gluconate, calcium lactate, potassiumchloride, potassium sulfate, sodium chloride, potassium fluoride, sodiumfluoride, ferrous lactate, ferrous gluconate, ferrous sulfate, ferrousfumurate and sodium lactate. The beneficial drugs are known to the artin Remington's Pharmaceutical Sciences, 14th Ed., 1970, published byMack Publishing Co., Easton, Penna.; and in The Pharmacological Basis ofTherapeutics, by Goodman and Gilman, 4th Ed., 1970, published by TheMacMillian Company, London.

The drug can also be in various forms, such as uncharged molecules,molecular complexes, pharmacologically acceptable salts such ashydrochlorides, hydrobromides, sulfate, laurylate, palmitate, phosphate,nitrate, borate, acetate, maleate, tartrate, oleate, and salicylate. Foracidic drugs, salts of metals, amines or organic cations, for examplequaternary ammonium can be used. Derivatives of drugs such as esters,ethers and amides which have solubility characteristic suitable for useherein can be used alone or mixed with other drugs. Also, a drug that iswater insoluble can be used in a form that is a water soluble derivativethereof to effectively serve as a solute, and on its release from thedevice, is converted by enzymes, hydrolyzed by body pH or othermetabolic processes to the original form, or to a biologically activeform. The agent can be in the reservoir as a solution, dispersion,paste, cream, particle, granule, emulsion, suspension or powder. Also,the agent can be mixed with a binder, dispersant, emulsifier or wettingagent and dyes.

The amount of agent present in the device is initially in excess of theamount that can be dissolved in the fluid that enters the reservoir.Under this physical state when the agent is in excess, the device willosmotically operate to give a substantially constant rate of release.The rate of agent release pattern can also be varied by having differentamounts of agent in the reservoir to form solutions containing differentconcentrations of agent for delivery from the device. Generally, thedevice can house from 0.05 ng to 5 grams or more, with individualdevices containing for example, 25 ng, 1 mg, 5 mg, 250 mg, 500 mg, 1.5g, and the like.

The solubility of an agent in an external fluid can be determined byvarious art known techniques. One method consists in preparing asaturated solution comprising the external fluid plus the agent asascertained by analyzing the amount of agent present in a definitequantity of the fluid. A simple apparatus for this purpose consists of atest tube of medium size fastened upright in a water bath maintained atconstant temperature and pressure, for example, one atmosphere, in whichthe fluid and agent are placed and stirred by a motor driven rotatingglass spiral. After a given period of stirring, a definite weight of thefluid is analyzed and the stirring continued for an additional period oftime. If the analysis shows no increase of dissolved agent aftersuccessive periods of stirring, in the presence of excess solid agent inthe fluid, the solution is saturated and the results are taken as thesolubility of the product in the fluid. If the agent is soluble, anadded osmotically effective compound optionally may not be needed; ifthe agent has limited solubility in the fluid, then an osmoticallyeffective compound can be incorporated into the device. Numerous othermethods are available for the determination of the solubility of anagent in a fluid. Typical methods used for the measurement of solubilityare chemical analysis, ultra violet spectometry, density, refractiveindex and electrical conductivity. Details of various methods fordetermining solubilities are described in United States Public HealthService Bulletin, No. 67 of the Hygienic Laboratory; Encyclopedia ofScience and Technology, Vol. 12, pages 542 to 556, 1971, published byMcGraw-Hill, Inc.; and Encyclopaedic Dictionary of Physics, Vol. 6,pages 547 to 557, 1962, published by Pergamon Press, Inc.

The devices of the invention are manufactured by standard techniques.For example, in one embodiment, the agent and other ingredients that maybe housed in the compartment and a solvent are mixed into a solid,semisolid or gel form by conventional methods such as ballmilling,calendering, stirring, or rollmilling and then pressed into apreselected shape. The wall forming the devices can be applied bymolding, spraying or dipping the pressed shape into wall formingmaterials. In another embodiment, a wall can be cast into a film, shapedto the desired dimensions, partially sealed to define a hollowcompartment that is filled with agent and then closed. The device alsocan be manufactured with an empty compartment that is filled through thepassageway. High frequency electronic techniques can be used to providedevices with walls having clean edges. Another, and presently preferred,technique that can be used is the air suspension procedure. Thisprocedure consists in suspending and tumbling the pressed agent in acurrent of air and the wall forming composite until the wall is appliedto the agent. The air suspension procedure is described in U.S. Pat. No.2,799,241; J. Am. Pharm. Assoc., Vol. 48, pages 451 to 459, 1959; andibid, Vol. 49, pages 82 to 84, 1960. Other standard manufacturingprocedures are described in Modern Plastics Encyclopedia, Vol. 46, pages62 to 70, 1969; and in Pharmaceutical Sciences, by Remingon, FourteenthEdition, pages 1626 to 1678, 1970, published by Mack Publishing Company,Easton, Penna.

The following examples are merely illustrative of the present invention,and they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those varied in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

The permeability of a series of walls formed of blends of materials wasillustrated by preparing and measuring their permeability to water asfollows: To a first mixture consisting of 76.6 parts of wall formingcellulose acetate having an acetyl content of 38.3% and 12.76 parts ofthe flux enhancer polyethylene glycol having a molecular weight of 400dissolved in a solvent consisting of 80 parts of methylene chloride and20 parts of methanol was added in small amounts and with continuousstirring a second mixture consisting of 8.52 parts hydroxybutylmethylcellulose which functions as both a stabilizer and a flux enhancerand 2.12 parts of the dispersant polyoxypropylene glycol having amolecular weight of 950 dissolved in a solvent consisting of 80 partsmethylene chloride and 20 parts of methanol and the stirring continueduntil the two mixtures were thoroughly blended. Then, an additionalsolvent consisting of 90 parts of acetone and 10 parts of water wasadded to the blend and all the materials stirred for 30 minutes at roomtemperature, 22° C, and atmosphere pressure until a homogeneouscomposite was formed.

Next, a film of 2.5 mils (dry thickness) of the composite was cast witha Gardner film-casting blade on a borosilicate glass substrate warmed to40° C. The film was dried while on the substrate in an oven at 70° C for120 hours. Then, the film was stripped from the substrate and it wasobserved to be optionally clear. The water transmission rate of the filmwas measured using potassium chloride and sodium acetazolamide in theosmosis cell at 37° C, and the results recorded in FIG. 10, discussedbelow.

EXAMPLE 2

The procedure of Example 1 was repeated in this example and allconditions were as described except that the film consisted of 68.10parts of cellulose acetate having an acetyl content of 38.3%, 17.02parts of hydroxybutyl methylcellulose, 12.76 parts of polyethyleneglycol having a molecular weight of 400 and 2.12 parts ofpolyoxypropylene glycol having a molecular wieght of 950. Thepermeability of the film to water using the same osmotic attractants wasmeasured and the results recorded in FIG. 10, discussed below.

EXAMPLE 3

The procedure of Example 1 was repeated in this example with allconditions as described except that the film consisted of 59.60 parts ofcellulose acetate having an acetyl content of 38.3%, 25.52 parts ofhydroxybutyl methylcellulose, 12.76 parts of polyethylene glycol havinga molecular weight of 400 and 2.12 parts of polyoxypropylene glycolhaving a molecular weight of 950. The permeability of the film to waterusing the same osmotic attractants was measured and the results recordedin FIG. 10.

In FIG. 10, the permeabilities through the films prepared according toExamples 1, 2 and 3 are plotted as a function of the hydroxybutylmethylcellulose content of the film. The numbers on the absicssarepresent the percent of wall stabilizer hydroxybutyl methylcellulose inthe three films, and the numbers or the ordinate represent thepermeability kπ (cm³.mil/cm².hr) through the films. The line with thecircles indicates potassium chloride as the osmotic attractant and thelines with triangles indicates sodium acetazolamide as the attractant.

EXAMPLE 4

The stability of a series of walls formed of blends of materials wasdemonstrated by preparing the walls and measuring their stability in thepresence of an osmotic attractant. The walls used were preparedaccording to the procedures of Examples 1, 2 and 3. Their stability wasdetermined by measuring their permeability to water using sodiumacetazolamide as the osmotic attractant in osmosis cells at 37° C. Theresults are plotted in FIG. 11. In the figure the numbers on theabsicssa represent the time in minutes the film is in contact with asaturated solution of sodium acetazolamide and the numbers on theordinate represent the water transmission rate, kπ (cm³.mil/cm². hr),through the film. The line with circles represents a film preparedaccording to Example 1. The line with triangles represents a filmprepared according to Example 2. The line with squares represents a filmprepared according to Example 3.

EXAMPLE 5

The inertness (physical and chemical stability) in the presence of acaustic-acting osmotic attractant, and the permeability to an aqueousmedium of a series of composite walls as a function of the degree ofsubstitution of the wall forming material and the concentration of thestabilizer and flux enhancer in the wall were determined by preparingand analyzing the walls according to the procedure of Example 1. Theresults obtained are presented in Table 3. In the table, the meaning ofthe terms and the abbreviations is as follows: the number in the columnheaded, "Walls", indicates a series of composite walls and the smallletters within a series indicates the different compositions ofparticular walls made in a series; the term "Composition" indicates thematerials and percent thereof for the walls; (the letters in a seriesrefer to embodiments of the compositions in a series and when they areused, they indicate an ingredient that is present in different amounts).In the table, the representations are as follows: in compositions 1through 3, the number 85.12 indicates the amount of cellulose acetate ora blend of cellulose acetate plus the amount of H.B.M.C. present in acomposition; the expression (85.12 - x)% indicates the percent celluloseacetate present as a single ingredient or as a blend of celluloseacetates, and x indicates the percent H.B.M.C. present in eachcomposition; in composition 4 the number 72.38 indicates the amount ofcellulose acetate plus the amount of P.E.G. present in a composition;the expresion (72.38 - x)% indicates the present cellulose acetatepresent, and x is the percent P.E.G.; "C.A." means cellulose acetate;"D.S." is the degree of substitution; "H.B.M.C." is hydroxybutylmethylcellulose; "P.E.G." and "polyethylene glycol" indicatepolyethylene glycol having a molecular weight of 400; "Polyoxypropyleneglycol" indicates the dispersant having a molecular weight of 950; "K₂SO₄ " is potassium sulfate having an osmotic pressure of 39 atmospheres;"T.M." is the caustic-acting osmotic attractant theophyllinemonoethanolamine having an osmotic pressure of 55 atmospheres; and "kπ"is the water transmission of the wall measured in cm³.mil/cm².hr.

                  TABLE 3                                                         ______________________________________                                                                     Osmotic                                          Wall    Composition          Attractant                                                                             kπ                                   ______________________________________                                        1     Cellulose acetate D.S. 1.75                                                   (85.12 - x)%, plus Polyethylene                                               glycol 12.76%, Polyoxypropylene                                               glycol 2.12%, and Hydroxybutyl                                                methylcellulose x%.                                                           a) C.A. 76.60% + H.B.M.C.  8.52%                                                                     K.sub.2 SO.sub.4                                                                       0.15                                          b) C.A. 68.10% + H.B.M.C. 17.02%                                                                     K.sub.2 SO.sub.4                                                                       0.20                                          c) C.A. 59.60% + H.B.M.C. 25.52%                                                                     K.sub.2 SO.sub.4                                                                       0.25                                    2     Cellulose acetate consisting                                                  of a blend of 67.19% Cellulose                                                acetate with D.S. 1.75 and 32.81%                                             Cellulose acetate with D.S. 2.3                                               (85.12 - x)%, plus Polyethylene                                               glycol 12.76%, Polyoxypropylene                                               glycol 2.12%, and Hydroxybutyl                                                methylcellulose x%.                                                           a) C.A. 76.60% + H.B.M.C.  8.52%                                                                     T.M.     0.13                                          b) C.A. 68.10% + H.B.M.C. 17.02%                                                                     T.M.     0.18                                          c) C.A. 59.60% + H.B.M.C. 25.52%                                                                     T.M.     0.215                                   3     Cellulose acetate consisting                                                  of a blend of 50% Cellulose                                                   acetate with D.S. 1.75 and 50%                                                Cellulose acetate with D.S. 2.3                                               (85.12 - x)%, plus Polyethylene                                               glycol 12.76%, Polyoxypropylene                                               glycol 2.12%, Hydroxybutyl                                                    methylcellulose x%.                                                           a) C.A. 76.60% + H.B.M.C.  8.52%                                                                     T.M.     0.1                                           b) C.A. 68.10% + H.B.M.C. 17.02%                                                                     T.M.     0.14                                          c) C.A. 59.60% + H.B.M.C. 25.52%                                                                     T.M.     0.17                                    4     Cellulose acetate D.S. 1.75,                                                  (72.38 - x)%, plus Hydroxy-                                                   butyl methylcellulose 25.5%,                                                  Polyoxypropylene glycol 2.12%,                                                and Polyethylene glycol, x%.                                                  a) C.A. 66.38% + P.E.G.  6.00%                                                                       K.sub.2 SO.sub.4                                                                       0.144                                         b) C.A. 59.63% + P.E.G. 12.75%                                                                       K.sub.2 SO.sub.4                                                                       0.24                                          c) C.A. 56.48% + P.E.G. 15.90%                                                                       K.sub.2 SO.sub.4                                                                       0.27                                          d) C.A. 46.88% + P.E.G. 25.50%                                                                       K.sub.2 SO.sub.4                                                                       0.31                                    5     64% Cellulose acetate blend of                                                67.19% Cellulose acetate with                                                 D.S. 1.75 and 32.81% Cellulose                                                acetate with D.S. 2.3, Hydroxy-                                                                      T.M.     0.19                                          butyl methylcellulose 22%,                                                    Polyethylene glycol 12%, and                                                  Polyoxypropylene glycol 2%.                                             ______________________________________                                    

EXAMPLE 6

The permeability of a film consisting of at least two cellulose acetateseach having a different acetyl content was determined by preparing afilm and measuring its permeability according to the procedure ofExample 1. The cellulose acetates used had an acetyl content rangingfrom 23% to 44.8% and the amount used ranged from 0.1% to 99.9% of acellulose acetate having an acetyl content of from 23% up to 32% andfrom 99.9% to 0.1% of a cellulose acetate having an acetyl content from32% up to 44.8%. A plurality of films were prepared according to theexample and they had the following composition:

(a) a film comprising 85.12% cellulose acetate blend consisting of67.19% cellulose acetate having an acetyl content of 32% and 32.81%cellulose acetate having an acetyl content of 38.3%, 12.76% polyethyleneglycol having a molecular weight of 400 and 2.12% polyoxypropyleneglycol having a molecular weight of 950;

(b) a film comprising 76.60% cellulose acetate of the blend as set forthin (a), polyethylene glycol and polyoxypropylene glycol the same as in(a), and additionally, 8.52% of hydroxybutyl methycellulose;

(c) a film comprising 68.10% cellulose acetate blend of (a),polyethylene glycol and polyoxypropylene glycol the same as (a), and17.02% of hydroxybutyl methylcellulose; and,

(d) a film comprising 59.60% cellulose acetate blend of (a),polyethylene glycol and polyoxypropylene glycol the same as (a), and25.52% of hydroxybutyl methylcellulose.

The ratio of the permeability of the films to water is plotted in FIG.12. In this figure, the numbers along the abscissa represent the percenthydroxybutyl methylcellulose in the film and the numbers along theordinate indicate the permeability ratio k/k_(o). The values for k/k_(o)were obtained by dividing the measured permeability of film (a) intoeach of (a), (b), (c), and (d) thereby expressing the permeability ratioof the films as a function of their hydroxybutyl methylcellulosecontent. In the figures, k_(o) is the permeability of the film to waterwith the film containing a zero concentration of H.B.M.C.

EXAMPLE 7

The fluid permeability of cellulose acetate films as a function of theacetyl content of each film in the presence of increasing amounts ofhydroxybutyl methylcellulose was determined by preparing a multiplicityof films and measuring their permeability to water. The films were madeand the water transmission of each film measured by following theprocedures of Examples 1 and 6. The results obtained were recorded inFIG. 13. In this figure the number along the abscissa represents theester content; that is, the percent acetyl content of the films, and thenumbers along the ordinate represent the fluid permeability k expressedas cm³.mil/cm².hr.atm through the films. The letters C_(o) through C₄indicate five series of films comprised of the following materials:C_(o) represents a plurality of films consisting of 100 percentcellulose acetate with acetyl contents ranging from 32 to 45 percent; C₁represents a plurality of films consisting of 85.12 percent celluloseacetate, 12.76 percent polyethylene glycol having a molecular weight of400 and 2.12 percent polyoxypropylene glycol having a molecular weightof 950; C₂ represents films consisting of 76.60% cellulose acetate, thesame amount of polyethylene glycol and polyoxypropylene glycol of C₁,and 8.52% hydroxybutyl methylcellulose; C₃ represents films consistingof 68.10 percent cellulose acetate, the same amount of polyethyleneglycol and polyoxypropylene glycol of C₁, and 17.02% hydroxybutylmethylcellulose; and C₄ represents films consisting of 59.60% celluloseacetate, the same amount of polyethylene glycol and polyoxypropyleneglycol as in C₁, and 25.52% of hydroxybutyl methylcellulose.

EXAMPLE 8

A plurality of films were prepared and their kπ values measured byfollowing the procedures of Examples 1 and 6. The results obtained wererecorded in Table 4. In the table, the abbreviations have the followingsignificance: C.A. indicates cellulose acetate; the numbers 32 to 38.3indicate in percent the acetyl content in the cellulose polymer; A_(o)indicates the film additionally contains 12.76 percent polyethyleneglycol having a molecular weight of 400 and 2.12 percentpolyoxypropylene glycol having a molecular weight of 950; A₁ indicatesthe film additionally contains the same amount of the polyethyleneglycol and polyoxypropylene glycol of A_(o) and it also contains 8.5percent hydroxybutyl methylcellulose; A₂ indicates the film additionallycontains the same amount of the polyethylene glycol and polyoxypropyleneglycol of A_(o) and it also contains 17.02% hydroxybutylmethylcellulose; A₃ indicates the film contains the polyethylene glycoland polyoxypropylene glycol of A_(o) and it also contains 25.52%hydroxybutyl methylcellulose; K₂ SO₄ is potassium sulfate; KCl ispotassium chloride; T.M. is theophylline monoethanolamine; the osmoticpressure π is in atmospheres; kπ is the volume of water transported perunit time through a film of unit thickness per unit area expressed ascm³.mil/cm².hr; k is water permeability in cm³. mil/cm².hr.π, obtainedby dividing kπ by π.

                  TABLE 4                                                         ______________________________________                                                  Osmotic   Osmotic                                                   Film      Attractant                                                                              Pressure π                                                                            kπ                                                                              k                                         ______________________________________                                        CA 32     K.sub.2 SO.sub.4                                                                        39         0.043                                                                              1.10 × 10.sup.-3                    CA 32     KCl       245        0.27 1.10 × 10.sup.-3                    CA 32     T.M.      55         0.06 1.09 × 10.sup.-3                    CA 32 + A.sub.0                                                                         K.sub.2 SO.sub.4                                                                        39         0.1  2.56 × 10.sup.-3                    CA 32 + A.sub.1                                                                         K.sub.2 SO.sub.4                                                                        39         0.15 3.84 × 10.sup.-3                    CA 32 + A.sub.2                                                                         K.sub.2 SO.sub.4                                                                        39         0.2  5.12 × 10.sup.-3                    CA 32 + A.sub.3                                                                         K.sub.2 SO.sub.4                                                                        39         0.25 6.41 × 10.sup.-3                    CA 34.06  KCl       245        0.165                                                                              6.73 × 10.sup.-4                    CA 34.06  T.M.      55         0.037                                                                              6.72 × 10.sup.-4                    CA 34.06 + A.sub.0                                                                      T.M.      55         0.085                                                                              1.50 × 10.sup.-3                    CA 34.06 + A.sub.1                                                                      T.M.      55         0.13 2.30 × 10.sup.-3                    CA 34.06 + A.sub.2                                                                      T.M.      55         0.18 3.27 ×  10.sup.-3                   CA 34.06 + A.sub.3                                                                      T.M.      55         0.215                                                                              3.90 × 10.sup.-3                    CA 35     T.M.      55         0.03 5.45 × 10.sup.-4                    CA 35     KCl       245        0.125                                                                              5.10 × 10.sup.-4                    CA 35 + A.sub.0                                                                         T.M.      55         0.07 1.27 × 10.sup.-3                    CA 35 + A.sub.1                                                                         T.M.      55         0.1  1.80 × 10.sup.-3                    CA 35 + A.sub.2                                                                         T.M.      55         0.14 2.50 × 10.sup.-3                    CA 35 + A.sub.3                                                                         T.M.      55         0.17 3.10 × 10.sup.-3                    CA 38     KCl       245        0.053                                                                              2.16 × 10.sup.-4                    CA 38.3 + A.sub.0                                                                       KCl       245        0.13 5.30 × 10.sup.-4                    Ca 38.3 + A.sub.1                                                                       KCl       245        0.19 7.70 × 10.sup.-4                    CA 38.3 + A.sub.2                                                                       KCl       245        0.26 1.06 × 10.sup.-3                    CA 38.3 + A.sub.3                                                                       KCl       245        0.32 1.31 × 10.sup.-3                    ______________________________________                                    

EXAMPLE 9

An osmotic therapeutic system for the controlled and continuous oralrelease of the beneficial agent sodium acetazolamide was made asfollows: to 138 grams of wall forming cellulose acetate having an acetylcontent of 32% was added 73.6grams of the stabilizer cellulose acetatehaving an acetyl content of 39.8%, 18.4 grams of the flux enhancerpolyethylene glycol of the formula H--OCH₂ CH₂ --OH wherein n is 8.2 to9.1 and 5520 grams of solvent consisting of acetone:water in the ratioof 88.5:11.5 and the materials blended in a commercially available highshear blender. The materials were blended at room temperature andatmospheric pressure for 30 minutes to produce a homogenous blend thathad a solid content of 4%.

Next, 170 grams of sodium acetazolamide and 8.5 grams of the binder 5%(polyvinylpyrrolidone) in isopropyl alcohol were blended in a standardv-blender for 45 minutes to produce wet granules. The granules weredried in an oven at 50° C for 48 hours and passed through a standard No.30 mesh sieve. Then, 1.8 grams of the lubricant magnesium stearate wereseparately passed through the No. 30 sieve and the former granules mixedwith the latter in the blender for about 30 minutes, or until a uniformmixture was obtained. The mixture was then compressed in a conventionalManesty tableting machine using a 5/16 inch diameter concave punch toproduce compressed tablets having a hardness of about 9 kg as measuredby a Strong-Cobb hardness tester.

Next, the above prepared wall forming composite and the tablets wereplaced in a Wurster air suspension machine and the tablets air tumbleduntil they were uniformly coated. The tablets were dried in an oven at50° C for one week to yield a final coat 5 mils thick weighing 21 mgs oneach tablet. Finally, a 5 mil aperture was mechanically drilled throughthe composite wall to produce the osmotic device with each containing170 mg of sodium acetazolamide, 8.5 mg of polyvinylpyrrolidone and 1.81mg of magnesium stearate. The in vitro release rate for the devices wasmeasured in a release rate machine that consisted of a series of testtubes with each tube containing 25 ml of distilled water at 37° C. Thetest was carried out by placing the devices in the first tubes for onehour, then the devices were transferred to the second tubes for onehour, and then with matching places into the remaining tubes. Thedevices were slowly oscillated throughout the test in the tubes. Theamount of acetazolamide released was measured spectrophotometrically at265 mμ at low pH. The device had a controlled and continuous rate ofrelease of about 18 mgs per hour over a prolonged period of 6 hours.

EXAMPLE 10

The procedure of Example 9 was repeated in this example with allconditions as described except that the wall of the device was formedessentially free of the stabilizer added in Example 9 to impartinertness to the wall in the presence of sodium acetazolamide. Thecomposition used to form the wall in this example consists of 218.5grams of cellulose acetate having an acetyl content of 32% and 11.5grams of polyethylene glycol having a molecular weight of 400 dissolvedin 5520 grams of the solvent methylene chloride:methanol mixed in theratio of 80:20. The amount of sodium acetazolamide released was measuredas previously described and the device had an increasing rate of releasefrom 10 to 35 mgs over up to three hours and a decreasing rate ofrelease from 35 to 8 mg from three hours up to six hours of releasetime.

EXAMPLE 11

A plurality of osmotic drug delivery devices are manufactured accordingto the procedure of Example 9 wherein the conditions were as describedexcept that the drug of Example 9 was replaced by an orallyadministrable drug selected from the group consisting of methazolamide,ethoxyolamide, diazepam, amitriptylene hydrochloride, imipraminehydrochloride, naicin, benzthiazide, chlorothiazide, tolbutamide,tolazamide, chloropropamide, procainamide hydrochloride, colchicine, andatropine.

EXAMPLE 12

An oral osmotic device for releasing the vitamin ascorbic acid in thegastrointestinal tract was manufactured as follows: first, a wallforming composition was prepared by thoroughly blending in a high shearblender for 45 minutes at 22.2° C and 1 atmosphere a batch consisting of61% cellulose acetate having an acetyl content of 32%, 29% celluloseacetate having an acetyl content of 38.3% and 10% polyethylene glycolhaving a molecular weight of 400 dissolved in acetone:water solventformulated on a 90:10 weight-by-weight ratio to produce a homogenouscomposite.

Next, 200 grams of ascorbic acid was slowly added to 10 grams ofethylcellulose in 100 milliliters of isopropyl alcohol and the materialsblended for 45 minutes to produce wet granules. The granules were driedat 50° C for 48 hours and then passed through a No. 20 mesh sieve. Then,the granules were lubricated with 1% magnesium stearate by mixing in ablender and after 30 minutes of blending they were passed through a No.20 sieve. The granules were then pressed into a solid mass using astandard tableting machine and a 14.8 mm diameter punch. The compressedmass had a finished hardness of 7 kg as measured by a Strong-Cobbhardness tester.

Next, the compressed mass and the wall forming composite were placed ina Wurster air suspension machine and the mass coated until each had acoat 4.7 mils thick. An osmotic passageway 7 mils thick was drilledthrough the wall to yield the osmotic device. Each device contained 400mgs of ascorbic acid and had a continuous release rate of about 30 mgsper hour over a period of 8 hours.

EXAMPLE 13

The procedure of Example 12 is repeated but ascorbic acid is replaced bynicotinamide, mannitol hexanitrate, isocarboxyazid, triamcinolone,tranylcypromine, meprobramate, malamide, salicylamide, or aspirin togive the corresponding osmotic device.

EXAMPLES 14 - 15

Two oral osmotic devices were manufactured following the procedure ofExample 9. The wall of each device consisted of a composite of 40%cellulose acetate having a 32% acetyl content, 40% cellulose acetatehaving an acetyl content of 38.3% and 20% polyethylene glycol having amolecular weight of 400. The compartment of one device contained 317 mgof aminophylline compounded with ethylenediamine having the equivalentof 250 mg of theophylline, 15.85 mg of poly(vinylpyrollidone) and 3.17mg of magnesium stearate. The wall of this device was 7.5 mils thick andthe device had a rate of release of about 18 mgs per hour through anosmotic passageway having a diameter of 7 mils. The compartment of theother device contained 333.3 mg of theophylline monoethanolamine havingan equivalency of 250 mg of theophylline, 16.67 mg ofpoly(vinylpyrrolidone), 9.5 mg of pharmaceutically acceptable red No. 3aluminum lake and 3.17 mg of magnesium stearate. The wall of this devicewas 7.5 mils thick and the device had a release rate of 22 mg per hourthrough an osmotic passageway having a diameter of 7 mils.

EXAMPLE 16

An osmotic device for releasing theophylline monoethanolamine over a sixhour period was manufactured using the above described procedures. Thewall of the device consisted of a composite of 22% hydroxybutylmethylcellulose, 43% cellulose acetate having a 32% acetyl content, 21%cellulose acetate having a 38.3% acetyl content, 12% polyethylene glycolhaving a molecular weight of 400 and 2% of polyoxypropylene glycolhaving a molecular weight of 950. The wall of the device was 5.7 milsthick, the osmotic port had a diameter of 10 mils, the compartmentcontained 125 mgs of theophylline present as monoethanolamine, and thedevice had a rate of release of 19 mgs per hour.

EXAMPLE 17

An osmotic device for releasing potassium chloride for a prolongedperiod of 12 hours was manufactured using the above described proceduresand apparatus. The wall of the device comprised a composite of 26%hydroxybutyl methylcellulose, 59% cellulose acetate having a 38.3%acetyl content, 13% polyethylene glycol having a molecular weight of 400and 2% polyoxypropylene glycol having a molecular weight of 950. Thewall of the device was 6 mils thick, the osmotic port had a diameter of10 mils and the compartment contained 750 mgs of potassium chloride.

The release rate for the device was measured in a bath that consisted ofa series of 12 tubes with each tube containing 25 ml of double distilledwater at 37.5° C. The test was carried out by placing the device in thefirst tube for one hour, then the device was transferred to the secondtube for one hour, and then with matching places into the remainingtubes. The devices were slowly oscillated throughout the test in thetubes containing the test solution. The amount of potassium chloridedelivered was determined by electrical conductive measurements for eachtube using a conductivity meter calibrated with known standards. Themeasured rate of release was about 55 mgs of potassium chloride per hourover a prolonged period of 12 hours.

The novel osmotic devices of this invention use means for the obtainmentof precise release rates in the environment of use while simultaneouslymaintaining the integrity of the device. While there has been describedand pointed out features of the invention as applied to presentlypreferred embodiments, those skilled in the art will appreciate thatvarious modifications, changes, additions and omissions in the devicesillustrated and described can be made without departing from the spiritof the invention.

What is claimed is:
 1. An osmotic device for dispensing a drug to ananimal comprising:(a) a shaped wall that is substantially inert andmaintains its physical and chemical integrity during the controlleddispensing of the drug comprising: (1) a semipermeable wall formingmaterial that is permeable to the passage of an external fluid andsubstantially impermeable to the passage of the drug, said semipermeablematerial being a polymer of the following formula ##STR4## wherein R₁,R₂, and R₃ are selected from the group consisting of hydrogen, alkyl,alkenyl, and acyl and n is greater than 5, and (2) a stabilizingmaterial that imparts inertness and stability to the wall, and whichstabilizing material is a different polymer of the following formula:##STR5## wherein R₅ is a member selected from the group consisting ofhydroxyl, alkoxy, hydroxyl-substituted alkoxy, alkylcarbonate,alkylcarbamate, alkylsulfonate, alkylsulfamate, and acyloxy, and n isgreater than 5; (b) a compartment formed by the shaped wall andcontaining the drug, said drug being a member selected from the groupconsisting of locally and systemically acting drugs; (c) a passageway inthe wall communicating with the compartment and the exterior of thedevice for dispensing the drug from the device; and, (d) wherein inoperation when the device is dispensing the drug to the animal, fluidtherefrom is continuously imbibed through the wall into the compartmentin a tendency towards osmotic equilibrium at a rate determined by thepermeability of the wall and the osmotic pressure gradient across thewall, thereby forming a solution containing drug which is dispensedthrough the passageway at a controlled rate, with the wall substantiallymaintaining its inertness and integrity in the presence of the drug andsolution thereof over a prolonged period of time.
 2. The osmotic devicefor dispensing a drug according to claim 1, wherein the device is sized,shaped and adapted as a dosage form for the administration of locallyand systemically acting drugs to the gastro-intestinal tract and thesemipermeable wall forming polymeric material has a degree ofsubstitution on its anhydroglucose groups greater than 0 and up to 3inclusive.
 3. The osmotic device for dispensing a drug according toclaim 1, wherein at least one of R₁, R₂ and R₃ is acyl and thesemipermeable wall forming material is a member selected from the groupconsisting of cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose propionate, cellulose acetate propionate, andcellulose acetate butyrate.
 4. The osmotic device for dispensing a drugaccording to claim 1, wherein the stabilizer material has a degree ofsubstitution on its anhydroglucose groups of greater than 0 and up to 3inclusive, and is a different material than the semipermeable wallforming material and which stabilizer material is a member selected fromthe group consisting of cellulose esters, cellulose ethers, mixedcellulose esters and ethers, cellulose acetate, cellulose diacetate,cellulose triacetate, hydroxyethyl methylcellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxybutyl cellulose, and hydroxybutyl methyl methylcellulose.
 5. Theosmotic device for dispensing a drug according to claim 1, wherein thecomposite wall contains a dispersant that blends the semipermeable andstabilizing materials into the stable wall, said dispersant being amember selected from the group consisting of an amphiphatic, anionic,cationic, nonionic and amphoteric dispersants selected from the groupconsisting of polyoxyalkylene glycols, esters of polyoxyalkyleneglycols, esters of polyhydric alcohols, sulfates esters, sulfatedamides, quaternary ammonium salts, alkanolamine fatty acids and tertiaryalkyl-ammonium salts.
 6. The osmotic device for dispensing a drugaccording to claim 1, wherein the shaped wall contains a plasticizerthat lowers the temperature of the second-order transition of the wall,is compatible with the materials forming the wall, increases theflexibility of the wall, and is non-toxic to animals.
 7. The osmoticdevice for dispensing a drug according to claim 1, wherein the shapedwall contains a plasticizer that lowers the temperature of thesecond-order transition of the wall, is compatible with the materialsforming the wall, increases the flexibility of the wall, is non-toxic toanimals, and is a member selected from the group consisting ofphthalates, phosphates, citrates, adipates, tartrates, sebacates,succinates, glycolates, glycerolates, benzoates, myristates,sulfonamides, and halogenated phenyls.
 8. The osmotic device fordispensing a drug according to claim 1, wherein the shaped wall has apermeability to the external fluid of 10⁻⁵ to 10⁻¹ cc mil/cm².hr.atm,and it contains a flux enhancer that assists in regulating thepermeability of the wall to the passage of external fluid, said fluxenhancer being a polyhydric alcohol.
 9. The osmotic device fordispensing a drug according to claim 1, wherein the shaped wall has apermeability to the external fluid of 10⁻⁵ to 10⁻¹ cc.mil/cm².hr.atm,and it contains a flux enhancer that assists in regulating thepermeability of the wall to the passage of external fluid, said fluxenhancer being a member selected from the group consisting of aliphaticdiols, polyalkylene glycols, poly(α,ω)-alkylenediols, esters of, andmixtures thereof.
 10. The osmotic device for dispensing drug accordingto claim 5, wherein the shaped wall contains from 0.001 to 50 parts of aflux enhancer that assists in regulating the fluid permeability of thewall and which flux enhancer is a member selected from the groupconsisting of hydrophilic and hydrophobic polyalkylene glycols,poly(α,ω)-alkylenediols, aliphatic diols and alkylene glycol esters. 11.The osmotic device for dispensing a drug according to claim 5, whereinthe shaped wall contains from 0.001 to 50 parts of a flux enhancer thatassists in regulating the fluid permeability of the wall and which fluxenhancer is an alkylene glycol.